2. Academic Validation
  3. Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

  • Bioorg Med Chem Lett. 2018 Jun 15;28(11):2029-2034. doi: 10.1016/j.bmcl.2018.04.063.
Sobhana Babu Boga 1,  Abdul-Basit Alhassan 2,  Alan B Cooper 2,  Ronald Doll 2,  Neng-Yang Shih 2,  Gerald Shipps 3,  Yongqi Deng 3,  Hugh Zhu 2,  Yang Nan 3,  Robert Sun 2,  Liang Zhu 3,  Jagdish Desai 2,  Mehul Patel 3,  Kiran Muppalla 3,  Xiaolei Gao 2,  James Wang 2,  Xin Yao 2,  Joseph Kelly 2,  Subrahmanyam Gudipati 2,  Sunil Paliwal 2,  Hon-Chung Tsui 2,  Tong Wang 3,  Bradley Sherborne 2,  Li Xiao 2,  Alan Hruza 2,  Alexei Buevich 2,  Li-Kang Zhang 2,  David Hesk 2,  Ahmed A Samatar 2,  Donna Carr 2,  Brian Long 2,  Stuart Black 2,  Priya Dayananth 2,  William Windsor 2,  Paul Kirschmeier 2,  Robert Bishop 2
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: [email protected].
  • 2 Discovery Chemistry, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • 3 Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
PMID: 29748051 DOI: 10.1016/j.bmcl.2018.04.063
Abstract

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).

Keywords

ATP competitive; ERK inhibitor; Kinase selectivity; MAP kinases; Oncology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112300
    ERK Inhibitor
    ERK